Skip to main content
SpringerLink
Log in

Cyclophosphamide analogues: synthesis, spectroscopic study, and antitumor activity of diazaphosphorinanes

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

Some diazaphosphorinanes were synthesized and characterized by 1H, 13C, 31P NMR and IR spectroscopy and elemental analysis. The antitumor activity of cyclophosphamide (CP) and its nine analogoues with formula , R = OC6H5CH3-4 (1), NHC6H4S(O)2NH2-4 (2), NHC(O)NHC6H4-CH3-2 (3), NHC(O)NHC6H4-NO2-2 (4), NHC(O)NHC6H4-NO2-3 (5), NHC(O)NHC6H4-NO2-4 (6), NHC(O)C6H4-NO2-2 (7), NHC(O)C6H4-NO2-3 (8), and NHC(O)C6H4-NO2-4 (9) were evaluated by cell culture on K562 cell line using MTT cell proliferation assay. The IC50 values for CP and the compounds 1–9 were in the range of 0.140 (for 3) to 58.250 μM (for 2). It was found that compounds 3–6 are the best candidates for antitumor activity close to CP. Compound 2 containing aminosulfonamide substituent is very much less toxic among these compounds.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Scheme 2

Similar content being viewed by others

References

  • Baldwin A, Huang Z, Jounaidi Y, Waxman DJ (2003) Identification of novel enzyme–prodrug combinations for use in cytochrome P450-based gene therapy for cancer. Archives Biochem Biophys 409:197–206. doi:10.1016/S0003-9861(02)00453-8

    Article  CAS  Google Scholar 

  • Billman JH, Meisenheimer JL, Awl RA (1964) 1,3,2-Diazaphosphorinane 2-oxides. 1. Synthesis of some 2-(N-arylamino)-1,3,2-diazaphosphorinane 2-oxides. J Med Chem 7:366–367. doi:10.1021/jm00333a032

    Article  PubMed  CAS  Google Scholar 

  • Borch RF, Canute GW (1991) Synthesis and antitumor properties of activated cyclophosphamide analogues. J Med Chem 34:3044–3052. doi:10.1021/jm00114a013

    Article  PubMed  CAS  Google Scholar 

  • Borch RF, Millard JA (1987) The mechanism of activation of 4-hydroxycyclophosphamide. J Med Chem 30:427–431. doi:10.1021/jm00385a029

    Article  PubMed  CAS  Google Scholar 

  • Borch RF, Liu J, Joswig C, Baggs RB, Dexter DL, Mangold GL (2001) Antitumor activity and toxicity of novel nitroheterocyclic phosphoramidates. J Med Chem 44:74–77. doi:10.1021/jm000359y

    Article  PubMed  CAS  Google Scholar 

  • D’Agostini C, Pica F, Febbraro G, Grelli S, Chiavaroli C, Garaci E (2005) Antitumour effect of OM-174 and cyclophosphamide on murine B16 melanoma in different experimental conditions. Int Immunopharmacol 5:1205–1212. doi:10.1016/j.intimp.2005.02.013

    Article  PubMed  Google Scholar 

  • Eliel E, Hutchins RO (1969) Conformational Analysis. XVIII. 1,3-dithianes. Conformational preferences of alkyl substituents and the chair-boat energy difference. J Am Chem Soc 91:2703–2715. doi:10.1021/ja01038a050

    Article  CAS  Google Scholar 

  • Flader C, Liu J, Borch RF (2000) Development of novel quinone phosphorodiamidate prodrugs targeted to DT-diaphorase. J Med Chem 43:3157–3167. doi:10.1021/jm000179o

    Article  PubMed  CAS  Google Scholar 

  • Gholivand K, Shariatinia Z, Pourayoubi M, Farshadian S (2005a) Syntheses and spectroscopic study of some new diazaphospholes and diazaphosphorinanes; crystal structure of . Z Naturforsch 60b:1021–1026

    Google Scholar 

  • Gholivand K, Pourayoubi M, Farshadian S, Molani S, Shariatinia Z (2005b) Synthesis and crystal structure of 5, 5-dimethyl-2-(p-methylanilino)-2-oxo-1,3,2-diazaphosphorinane. Anal Sci 21:x55. doi:10.2116/analscix.21.x55

    CAS  Google Scholar 

  • Gholivand K, Pourayoubi M, Shariatinia Z (2007) 2, 3J(P, X) [X = H, C] coupling constants dependency to the ring size, hybridization and substituents in new diazaphospholes and diazaphosphorinanes, NMR and X-ray crystallography studies. Polyhedron 26:837–844. doi:10.1016/j.poly.2006.09.092

    Article  CAS  Google Scholar 

  • Gholivand K, Dorosti N (2010) Synthesis, spectroscopic characterization, crystal structure, theoretical studies and antibacterial evaluation of two novel N-phosphinyl urease. Monatshefte Chemie-Chemical Monthly

  • Gholivand K, Mostaanzadeh H, Vedova COD (2010) J Mol Struct, in preparation

  • Hansch C, Muir RM, Fujita T, Maloney PP, Geiger F, Streich M (1963) The correlation of biological activity of plant growth regulators and chloromycetin derivatives with Hammett constants and partition coefficients. J Am Chem Soc 85:2817–2824. doi:10.1021/ja00901a033

    Article  CAS  Google Scholar 

  • Jackman LM, Sternhell S (1969) Nuclear magnetic resonance spectroscopy in organic applications of chemistry. Pergamon Press, London, pp 238–240

    Google Scholar 

  • Jian M, Kwon C-H (2003) 1,2-Benzisoxazole phosphorodiamidates as novel anticancer prodrugs requiring bioreductive activation. J Med Chem 46:5428–5436. doi:10.1021/jm020581y

    Article  Google Scholar 

  • Khalikova TA, Ya Zhanaeva S, Korolenko TA, Kaledin VI, Kogan G (2005) Regulation of activity of cathepsins B, L, and D in murine lymphosarcoma model at a combined treatment with cyclophosphamide and yeast polysaccharide. Cancer Lett 223:77–83. doi:10.1016/j.canlet.2004.10.028

    Article  PubMed  CAS  Google Scholar 

  • Li Z, Han J, Jiang Y, Browne P, Knox RJ, Hu L (2003) Nitrobenzocyclophosphamides as potential prodrugs for bioreductive activation: synthesis, stability, enzymatic reduction, and antiproliferative activity in cell culture. Bioorg Med Chem 11:4171–4178. doi:10.1016/S0968-0896(03)00459-0

    Article  PubMed  CAS  Google Scholar 

  • Ludeman SM, Zon G, Egan W (1979) Synthesis and antitumor activity of cyclophosphamide analogues. 2.1 Preparation, hydrolytic studies, and anticancer screening of 5-bromocyclophosphamide, 3,5-dehydrocyclophosphamide, and related systems. J Med Chem 22:151–158. doi:10.1021/jm00188a006

    Article  PubMed  CAS  Google Scholar 

  • McNeish IA, Searle PF, Young LS, Kerr DJ (1997) Gene directed enzyme prodrug therapy for cancer. Adv Drug Deliv Rev 26:173–184. doi:10.1016/S0169-409X(97)00033-1

    Article  PubMed  CAS  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63. doi:10.1016/0022-1759(83)90303-4

    Article  PubMed  CAS  Google Scholar 

  • Niculescu-Duvaz I, Springer CJ (1997) Antibody-directed enzyme prodrug therapy (ADEPT): a review. Adv Drug Deliv Rev 26:151–172. doi:10.1016/S0169-409X(97)00032-X

    Article  PubMed  CAS  Google Scholar 

  • Olyyai R, Stella VJ (1993) Prodrugs of peptides and proteins for improved formulation and delivery. Ann Rev Pharmacol Toxicol 33:521–544. doi:10.1146/annurev.pa.33.040193.002513

    Article  Google Scholar 

  • Pochopoin NL, Charman WN, Stella VJ (1995) Amino acid derivatives of dapsone as water-soluble prodrugs. Int J Pharm 121:157–167. doi:10.1016/0378-5173(95)00005-4

    Article  Google Scholar 

  • Reedijk J (1996) Improved understanding in platinium antitumour chemistry. Chem Commun 801–806. doi: 10.1039/CC9960000801

  • Senter PD, Svensson HP (1996) A summary of monoclonal antibody-enzyme/prodrug. Adv Drug Deliv Rev 22:341–349. doi:10.1016/S0169-409X(96)00445-0

    Article  CAS  Google Scholar 

  • Sherwood RF (1996) Advanced drug delivery reviews: enzyme prodrug therapy. Adv Drug Deliv Rev 22:269–288. doi:10.1016/S0169-409X(96)00450-4

    Article  CAS  Google Scholar 

  • Springer CJ, Niculescu-Duvaz I (1996) Gene-directed enzyme prodrug therapy (GDEPT): choice of prodrugs. Adv Drug Deliv Rev 22:351–364. doi:10.1016/S0169-409X(96)00449-8

    Article  CAS  Google Scholar 

  • Tobias SC, Borch RF (2001) Synthesis and biological studies of novel nucleoside phosphoramidate prodrugs. J Med Chem 44:4475–4480. doi:10.1021/jm010337r

    Article  PubMed  CAS  Google Scholar 

  • Tolkimth H (1959) (Dow Chem. Co., Midland, Mich.). Electron group polarizability and molecular properties of organophosphorus compounds. Ann NY Acad Sci 79:189–232. doi: 10.1111/j.1749-6632.1959.tb42781.x

  • Software for Windows, GraphPad Software Inc., SanDiego, CA. http://www.graphpad.com

Download references

Acknowledgments

We wish to thank the Research Office of Tarbiat Modares University for the financial support of this work.

Author information

Authors and Affiliations

  1. Department of Chemistry, Faculty of Basic Sciences, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran

    Khodayar Gholivand, Nilufar Dorosti & Fatemeh Ghaziany

  2. Department of Chemistry, Amirkabir University of Technology, P.O. Box 159163-4311, Tehran, Iran

    Zahra Shariatinia

  3. Department of Biochemistry, Faculty of Biology, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran

    Sina Sarikhani & Manouchehr Mirshahi

Authors
  1. Khodayar Gholivand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nilufar Dorosti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zahra Shariatinia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fatemeh Ghaziany
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sina Sarikhani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Manouchehr Mirshahi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Khodayar Gholivand.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gholivand, K., Dorosti, N., Shariatinia, Z. et al. Cyclophosphamide analogues: synthesis, spectroscopic study, and antitumor activity of diazaphosphorinanes. Med Chem Res 20, 1287–1293 (2011). https://doi.org/10.1007/s00044-010-9466-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-010-9466-3

Keywords

Search

Navigation